NLRX1 acts as tumor suppressor by regulating TNF-α induced apoptosis and metabolism in cancer cells

• NLRX1 sensitizes cancer cells to TNF induced cell death by regulating Caspase-8.
• NLRX1 localizes to mitochondria (mt) and regulates TNF induced mt-ROS generation.
• Mitochondrial association of Caspase-8 with NLRX1 may regulate mt-ETC function.
• NLRX1 expression in cancer cells suppresses tumorigenicity in nude mice.

Chronic inflammation in tumor microenvironment plays an important role at different stages of tumor development. The specific mechanisms of the association and its role in providing a survival advantage to the tumor cells are not well understood. Mitochondria are emerging as a central platform for the assembly of signaling complexes regulating inflammatory pathways, including the activation of type-I IFN and NF-κB. These complexes in turn may affect metabolic functions of mitochondria and promote tumorigenesis. NLRX1, a mitochondrial NOD-like receptor protein, regulate inflammatory pathways, however its role in regulation of cross talk of cell death and metabolism and its implication in tumorigenesis is not well understood. Here we demonstrate that NLRX1 sensitizes cells to TNF-α induced cell death by activating Caspase-8. In the presence of TNF-α, NLRX1 and active subunits of Caspase-8 are preferentially localized to mitochondria and regulate the mitochondrial ROS generation. NLRX1 regulates mitochondrial Complex I and Complex III activities to maintain ATP levels in the presence of TNF-α. The expression of NLRX1 compromises clonogenicity, anchorage-independent growth, migration of cancer cells in vitro and suppresses tumorigenicity in vivo in nude mice. We conclude that NLRX1 acts as a potential tumor suppressor by regulating the TNF-α induced cell death and metabolism.